Silver(I) triflate-catalyzed protocol for the post-ugi synthesis of spiroindolines

A silver(I) triflate-catalyzed protocol for the post-Ugi synthesis of tetracyclic spiroindolines has been developed. The protocol worked best for indole-3-carbaldehyde-derived Ugi adducts obtained using anilines and 3-aryl propiolic acids. Thus, it is complementary to the previous cationic gold-catalyzed procedure that was developed for analogues Ugi substrates derived from aliphatic amines and 3-alkyl propiolic acids. Furthermore, we have demonstrated that under our new settings this domino Friedel-Crafts ipso cyclization / imine trapping process could be efficiently combined with the preceding four-component Ugi reaction into a two-step one-pot transformation

Antibiotic use during pregnancy and neurodevelopmental outcomes of offspring in early childhood

There is limited research on the effects of antibiotic use during pregnancy on neurodevelopmental outcomes of offspring in early childhood. The aim of this study was to investigate associations between antibiotic use during early pregnancy and neurodevelopmental outcomes, both behavioral and cognitive, in the offspring during early childhood. This thesis examined a longitudinal study of 570 mother-child pairs where prenatal exposures and at least one neurodevelopment outcome assessment were recorded. An interview was conducted with mothers on average one year after delivery to collect information on prenatal exposures. Neurodevelopmental outcomes were assessed between the ages 5–11 years using the cognitive-based outcomes of Peabody Picture Vocabulary Test (PPVT-III) and the Beery-Buktenica Test of Visual Motor Integration-Fifth Edition (VMI-5) and behavioral-based outcomes of the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF). Adjusted mean differences (adjMD) in outcome measures were calculated between mothers reporting antibiotics use and mothers reporting treated infections. Antibiotic use during pregnancy was not significantly associated with the two cognitive measures but was associated with increased total behavioral problems reported by mothers (adjMD: 2.60; CI: 0.50, 4.69) and teachers (adjMD 2.60; 95% CI 0.44, 4.76). Overall, antibiotics use during pregnancy was not associated with differences in childhood cognition but may be associated with greater behavior problems

Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase

Uracil-DNA glycosylase (UDG) compromises the replication strategies of diverse viruses from unrelated lineages. Virally encoded proteins therefore exist to limit, inhibit or target UDG activity for proteolysis. Viral proteins targeting UDG, such as the bacteriophage proteins ugi, and p56, and the HIV-1 protein Vpr, share no sequence similarity, and are not structurally homologous. Such diversity has hindered identification of known or expected UDG-inhibitory activities in other genomes. The structural basis for UDG inhibition by ugi is well characterized; yet, paradoxically, the structure of the unbound p56 protein is enigmatically unrevealing of its mechanism. To resolve this conundrum, we determined the structure of a p56 dimer bound to UDG. A helix from one of the subunits of p56 occupies the UDG DNA-binding cleft, whereas the dimer interface forms a hydrophobic box to trap a mechanistically important UDG residue. Surprisingly, these p56 inhibitory elements are unexpectedly analogous to features used by ugi despite profound architectural disparity. Contacts from B-DNA to UDG are mimicked by residues of the p56 helix, echoing the role of ugi’s inhibitory beta strand. Using mutagenesis, we propose that DNA mimicry by p56 is a targeting and specificity mechanism supporting tight inhibition via hydrophobic sequestration

Ugi multicomponent reaction to prepare peptide–peptoid hybrid structures with diverse chemical functionalities

Monodisperse sequenced peptides and peptoids present unique nano-structures based on their self-assembled secondary and tertiary structures. However, the generation of peptide and peptoid hybrid oligomers in a sequence-defined manner via Ugi multicomponent reaction has not yet been studied. Herein, we report a synthetic strategy that enables both the modification of peptides as well as the generation of sequence-defined peptide–peptoid hybrid structures. Our synthetic methodology rests on the fusion of solid phase peptide synthesis with Ugi multicomponent reactions. We evidence that a diversity of chemical functionalities can be inserted into peptides or used in the design of peptide–peptoid hybrids exploiting a wide functional array including amines, carboxylic acids, hydrocarbons, carbohydrates as well as polymers, introducing a sequence-defined synthetic platform technology for precision peptoid hybrids

Morphology of the Esophageal Hiatus: Is It Different in 3 Types of Hiatus Hernias?

Background/aimsThe esophageal hiatus is formed by the right crus of the diaphragm in the majority of subjects. Contraction of the hiatus exerts a sphincter-like action on the lower esophageal sphincter (LES). The aim is to study the hiatal anatomy (using CT scan imaging) and function (using high-resolution manometry [HRM]), and esophageal motor function in patients with sliding and paraesophageal hiatal hernia.MethodsWe assessed normal subjects (n = 20), patients with sliding type 1 hernia (n = 18), paraesophageal type 2 hernia (n = 19), and mixed type 3 hernia (n = 19). Hernia diagnosis was confirmed on the upper gastrointestinal series. The hiatal morphology was constructed from the CT scan images. The LES pressure and relaxation, percent peristalsis, bolus pressure, and hiatal squeeze pressure were assessed by HRM.ResultsThe CT images revealed that the esophageal hiatus is formed by the right crus of the diaphragm in all normal subjects and 86% of hernia patients. The hiatus is elliptical in shape with a surface area of 1037 mm2 in normal subjects. The hiatal dimensions were larger in patients compared to normal subjects. The HRM revealed impaired LES relaxation and higher bolus pressure in patients with paraesophageal compared to the sliding hernia. The hiatal pinch on HRM was recognized in significantly higher number of patients with sliding as compared to paraesophageal hernia.ConclusionsUsing a novel approach, we provide details of the esophageal hiatus in patients with various kinds of hiatal hernia. Impaired LES relaxation in paraesophageal hernia may play a role in its pathophysiology and genesis of symptoms

Open Notebook Science Challenge: Solubilities of Organic Compounds in Organic Solvents

This book contains the results of the Open Notebook Science Solubility Challenge. All experimental measurements are provided with a link to either the laboratory notebook page where the experiment was carried out or to a literature reference. The Challenge was sponsored by Submeta, Nature and Sigma-Aldrich

Open Notebook Science Challenge: Solubilities of Organic Compounds in Organic Solvents

This book contains the results of the Open Notebook Science Solubility Challenge. All experimental measurements are provided with a link to either the laboratory notebook page where the experiment was carried out or to a literature reference. The Challenge was sponsored by Submeta, Nature and Sigma-Aldrich